In diverse organisms, a common mesendodermal tissue field gives rise to the endoderm and a mesoderm subset that forms the heart and blood in vertebrates. In the nematode Caenorhabditis elegans, mesendodermal development is initiated by the maternally expressed transcription factor SKN-1, which specifies the fate of a single cell, the EMS blastomere. The EMS daughter cell E becomes the endoderm, which consists of the intestine. Its sister cell MS gives rise to mesodermal derivatives that include the pharynx, a feeding pump that is analogous to the heart, and coelomocytes that resemble macrophages. In these embryonic cells SKN-1 induces expression of the GATA factors MED-1 and MED-2, which are required for differentiation of EMS lineages. C. elegans skn-1 mutants are sensitive to oxidative stress and have shortened lifespans.
In vertebrates, Nrf proteins activate transcription of genes encoding the Phase II detoxification enzymes, which constitute the primary cellular defense against oxidative stress. Essentially all organisms must defend themselves against reactive oxygen species (ROS), which are derived from both mitochondrial respiration and exogenous sources. Phase II enzymes synthesize the critical reducing agent glutathione, scavenge ROS directly, and detoxify reactive intermediates that are generated when xenobiotics are metabolized by the cytochrome p450 (Phase I) enzymes. Through Nrf2, exposure to oxidative stress or particular classes of chemicals induces Phase II enzyme gene expression in a variety of tissues, including the liver and digestive tract. This mechanism also constitutes the major response to chemoprotective antioxidants, including many natural compounds, which thereby stimulate xenobiotic detoxification and inhibit carcinogen-induced tumorigenesis. Accordingly, mice that lack Nrf2 are abnormally susceptible to drug toxicity and carcinogenesis, and do not respond to chemoprotective antioxidants.